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Involvement of the Ventrolateral Periaqueductal Gray Matter-Central Medial Thalamic Nucleus-Basolateral Amygdala Pathway in Neuropathic Pain Regulation of Rats.

ABSTRACT: The central medial nucleus (CM), a prominent cell group of the intralaminar nuclei (ILN) of the thalamus, and the ventrolateral periaqueductal gray matter (vlPAG) are two major components of the medial pain system. Whether vlPAG and CM are input sources of nociceptive information to the basolateral amygdala (BLA) and whether they are involved in neuropathic pain regulation remain unclear. Clarifying the hierarchical organization of these subcortical nuclei (vlPAG, CM, and BLA) can enhance our understanding on the neural circuits for pain regulation. Behavioral test results showed that a CM lesion made by kainic acid (KA) injection could effectively alleviate mechanical hyperalgesia 4, 6, and 8 days after spared nerve injury (SNI) surgery, with the symptoms returning after 10 days. Morphological studies revealed that: (1) the CM received afferents from vlPAG and sent efferents to BLA, indicating that an indirect vlPAG-CM-BLA pathway exists; (2) such CM-BLA projections were primarily excitatory glutamatergic neurons as revealed by fluorescence in situ hybridization; (3) the fibers originated from the CM-formed close contacts with both excitatory and inhibitory neurons in the BLA; and (4) BLA-projecting CM neurons expressed Fos induced by SNI and formed close contacts with fibers from vlPAG, suggesting that the vlPAG-CM-BLA indirect pathway was activated in neuropathic pain conditions. Finally, the vlPAG-CM-BLA indirect pathway was further confirmed using anterograde and monosynaptic virus tracing investigation. In summary, our present results provide behavioral and morphological evidence that the indirect vlPAG-CM-BLA pathway might be a novel pain pathway involved in neuropathic pain regulation.

SUBMITTER: Sun Y

PROVIDER: S-EPMC7394700 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Involvement of the Ventrolateral Periaqueductal Gray Matter-Central Medial Thalamic Nucleus-Basolateral Amygdala Pathway in Neuropathic Pain Regulation of Rats.

Sun Yi Y Wang Jian J Liang Shao-Hua SH Ge Jun J Lu Ya-Cheng YC Li Jia-Ni JN Chen Yan-Bing YB Luo Dao-Shu DS Li Hui H Li Yun-Qing YQ

Frontiers in neuroanatomy 20200721

The central medial nucleus (CM), a prominent cell group of the intralaminar nuclei (ILN) of the thalamus, and the ventrolateral periaqueductal gray matter (vlPAG) are two major components of the medial pain system. Whether vlPAG and CM are input sources of nociceptive information to the basolateral amygdala (BLA) and whether they are involved in neuropathic pain regulation remain unclear. Clarifying the hierarchical organization of these subcortical nuclei (vlPAG, CM, and BLA) can enhance our un ...[more]

PMID: 32792913

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Project description:As one of the thalamic midline nuclei, the thalamic paraventricular nucleus (PVT) is considered to be an important signal integration site for many descending and ascending pathways that modulate a variety of behaviors, including feeding, emotions, and drug-seeking. A recent study has demonstrated that the PVT is implicated in the acute visceral pain response, but it is unclear whether the PVT plays a critical role in the central processing of chronic pain. Here, we report that the neurons in the posterior portion of the PVT (pPVT) and their downstream pathway are involved in descending nociceptive facilitation regarding the development of neuropathic pain conditions in male rats. Lesions or inhibition of pPVT neurons alleviated mechanical allodynia induced by spared nerve injury (SNI). The excitability of pPVT-central amygdala (CeA) projection neurons was significantly increased in SNI rats. Importantly, selective optogenetic activation of the pPVT-CeA pathway induced obvious mechanical hypersensitivity in naive rats. In addition, we used rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques to define a novel neuronal circuit in which glutamatergic neurons in the vlPAG were the target of the pPVT-CeA descending facilitation pathway. Our data suggest that this pPVTGlu+-CeA-vlPAGGlu+ circuit mediates central mechanisms of descending pain facilitation underlying persistent pain conditions.SIGNIFICANCE STATEMENT Studies have shown that the interactions between the posterior portion of the thalamic paraventricular nucleus (pPVT) and central amygdala (CeA) play a critical role in pain-related emotional regulation. However, most reports have associated this circuit with fear and anxiety behaviors. Here, an integrative approach of behavioral tests, electrophysiology, and immunohistochemistry was used to advance the novel concept that the pPVT-CeA pathway activation facilitates neuropathic pain processing. Using rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques, we found that glutamatergic neurons in the vlPAG were the target of the pPVT-CeA pathway. Thus, this study indicates the involvement of a pPVTGlu+-CeA-vlPAGGlu+ pathway in a descending facilitatory mechanism underlying neuropathic pain.

Project description:IntroductionResting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN).MethodsIn 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN.ResultsOf all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.

Dataset Information

Involvement of the Ventrolateral Periaqueductal Gray Matter-Central Medial Thalamic Nucleus-Basolateral Amygdala Pathway in Neuropathic Pain Regulation of Rats.

Publications

Involvement of the Ventrolateral Periaqueductal Gray Matter-Central Medial Thalamic Nucleus-Basolateral Amygdala Pathway in Neuropathic Pain Regulation of Rats.

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